Peripheral blood leukocytes (PBL) from HTLV-III antibody (+) and (-) donors were tested for IL-2 production and cell-mediated lympholysis (CML) to recall antigens (S+X) and to HLA allogeneic cells (ALLO). Among antibody (+) donors, approximately 50% failed to respond to S+X, whereas all responded to ALLO, except patients in the critical stages of AIDS, who responded to neither type of immunogen. Using PBL from antibody (-) donors we demonstrated by cell fractionation techniques that S+X T cell responses are obliged to use CD4+ T cells, whereas ALLO responses can be generated by either CD4+ or CD4- T cells. Thus, the selective loss of S+X responses probably reflects the loss of CD4+ cells during AIDS development. By studying the T helper cell responses in 80 HIV+ patients without AIDS, we have been able to subdivide Walter Reed Stage 1 patients into three subgroups: those that have lost no T helper cell (T/H) function; those that have lost only TH to S+X; and those that have lost TH function for both S+X and ALLO. We have not seen evidence for a defect in antigen-presenting cell function.